Preparation of alkylaminoalkanethiols



Patented May 28, 1946 amnesia .PRlil'ARATIoN F 1m r it LKANETnr v MarkWendell Far No, Drawing sclaims. cease-58s) p This mates rest teallrylaminoalkanejthiols. More particularly, it relates to: a processfor preparing alkylaminoalkanethiols..

.Alkylaminoalkanethiols, either as .suchjia in the form or derivatives;s en; as. salts, thioethra, etc., are of importance inthe pharmaceuticalindustry because of their physiological activity. They have heretoforebeen butlittle investigated,

chiefly because theprocesses proposed for their preparation have notbeen entirely satisfactory.

An object of this invention is to provide a general process for thepreparation of alkylaminoalkanethiols. Another object is to provide aproc-j ess giving alnlaminoalkanethiols of good purity. A more specificobject is the preparation of gamma-dialkylaminopropane thiols. jectswill appear hereinafter.

These objects are accomplished by the present invention, which comprisesreacting preferably at least three moles of an alkylamine, preferably alower alkylamine, having hydrogien on the thio group by at'least twocarbon atoms.

The process is illustrated by the equation;

Preferably, the reaction is continued until there is n furtherseparation of amine hydrochloride. e latter is removed from the reactionmixture and the alkiaminoalkanethiol is separated from the amideby-product by appropriate procedures.

The more detailed practice of the invention is illustrated by thefollowing examples, wherein parts given are by weight. There are, ofcourse,

many forms of the invention other than these specific embodiments.

Example I A solution of 90 parts of diethylamine and 52 parts ofbeta-chloroethanethiol acetate (prepared by reacting thiolacetic acidwith vinyl chloride accordin to the process described in Ellingboeapplication Serial No. 476,625, filed February 20,- 1943, in 150 partsof anhydrous other is sealed in a pressure vessel and heated foreighteen hours at 100' C. The vessel is cooled, the diethylamine 0hydrochloride filtered of! and the filtrate separated into itscomponents by fractional distillation. There is obtained 32 parts ofbeta-diethylamlnoethanethiol (yield: 64% of theory) boiling at 64-65 C.at 20 mm. and 29 parts of N, N-diethylacetamide boilingat 80 0. M20 55are preferred. Since the halogen of the acylthio- Other ob-i aminonitrogen with one mole of an acylthioalkyl halide, preferably anacylthio lower alkyl halide, a in which the halogen is separated fromthe acyll its." that..." rattan: ai ivaliit or (126, as determined'bytitration:witlistandard acid in .the presence of Methyl and it contains26.5% of, thiol sulfur ,as determined. by titration with e 'fiiefiqfztrese 5 standard iodine solutlonfl' l'he]calculated values 11101 acetate(prepared ,pyireactmg thioljacetic acid with allylchloride accordingtcSiiiberg, Ber. 743.64, (1941))jand 300 parts 101 diethylamlne are mixedandhea'ted in a pressure vessel at1-00 C. for 18 hours. The product,after removal of the diethylamine hydrochoride gives on distillationdiethylamine and a mixture (103 parts) of vN,N --ciiethylacetamidc andgamma-diethylaminopropanethiol. Since thismixture cannot be separated bydistillation, it is dissolved in 200 parts :0 of 50% aqueous potassiumhydroxide, and the .ciiethylacetamiozie is removed by repeatedextraction with ether. The aqueous layer is then neutralized with carbondioxide, the oil which separates is extracted with ether, dried anddistilled.

28 There is obtained parts (yield: 23% cfthecry) oigamma-diethylaminopropanethiol, boiling at '75-'l6 C. at 20 mm. Thethiol has a neutral equivalent of 148 and contains 21.8% of thiol"sulfur. The calculated values are 147 'and 21.4,

respectively. The process is applicable to any alkaylamine havinghydrogen on amino nitrogen, 1 such as methylamine, ethylamine,butylamine, isobutyl amine, octylamine, dodecylamine, hexadecylamine,octadecylamine, diisopropylamine, dicyclo hexylamine, dihexylamine,dimethylamine, dia Lower ,alkylamines are pre-.

' ferred. Mixtures of amines can be used. in which butylamine, etc.

case two or more alkylaminoalkanethiols areiobtained. The secondaryalkylamines react more cleanly and give better yields than the primaryones and they are therefore preferred. The other reactant maybe anyaliphatic, acylthioalkyl halide in which the halogen is removed from theacyli an acetylthioalkyl halide since the acylthio group is consumed inthe reaction and does. not appear in the final product. Acylthio loweralkyl halides Rosanna-sadis s anna-enamel fithio group by at least twocarbons, such as betabromopropanethiol acetate, beta-chlorobutanethiolacetate, gamma-bromopentanethiol acetate,

alkyl halide is removed as a byproduct, it is preferred thatacylthioalkyl halides wherein the halogen is of atomic weight between 30and 80, and preferably chlorides, be used.

Preferably at least three moles of the amine are used per mole of theacylthioalkyl halide, in order to insure complete reactionof-the'l'atter which, in general, is the more expensive reactant.However, less than three moles of amine may be used, if desired. Thereaction time and temperature may vary according to the reactantsselected,

but there is no difficulty in ascertaining the best reaction conditions.In general, elevated. temperatures, e. g. 75-150 C., are used since at,ordi nary temperatures the reaction may be undesirably slow. It ispreferable to continue the reaction until there is no further separationof b Although the reaction will proceed satisfactorily in the absence ofa solvent,-

amine hydrohalide.

the use of a solvent facilitates the removal oi the amine hydrohalideand is therefore preferable.

Suitable solvents are water, methanol, ethanol,

ether, benzene or an excess of theamine. 10f this group the last threeare preferredbecause they are essentially nonsolvents for 'aminesalts.

In addition to their usefulness as therapeutic agents, thealkylaminoalkanethiols are valuable intermediates in organic synthesesdnview of the presence of two reactive groups, one acidicand one basic, inthe same molecule. V I v The term lower alkyl" is used to denote anlalkylgroup of one to seven carbon atoms. Thus ,ing' at 75 150 C.gamma-chloropropanethiol acetate with atleast three moles, per mole ofacylthioalkyl halide, of diethylamine and isolating thegamma-diethylaminopropanethiol.

2. Process for the preparation of an N,N-diethyl-aminoalkanethiol whichcomprises heating at least three mols of diethylamine at a temperatureof to 150 C., with one molof a chloroalkyl thiolacetate having thechlorine from two to ten carbons removed from the acetylthio group untilthe diethylaminoalkanethiol is formed and isolating thediethylaminoalkanethiol formed.

3. Process for the preparation of N,N-diethylaminoethanethiol whichcomprises heating at least three mols of diethylamine at a temperatureof 75 to C. with one mol of beta-chloroethyl thiolacetate and isolatingthe diethylaminoethanethiol formed.

- MARK WENDELL FARLOW.

